Tolerance to morphine is characterized by compensatory adaptive changes that occur in neurons that express the mu-opioid receptor or in neural circuits in which these neurons participate. The state of tolerance is hypothesized to result in a hyperexcitability of neurons which can be unmasked upon injection of an opiate antagonist, termed "latent sensitization." This heightened response requires the activation of NMDA receptors, as well as second messenger pathways that include PKA, PKC, and NO production. These same cellular responses have been implicated in the development of injury-induced increased excitability of neurons in the dorsal horn of the spinal cord, or spinal central sensitization, which in many respects parallels morphine tolerance. In fact, an NMDA-dependent morphine tolerance occurs in the same site of action. Recently, a contribution of the auto-phosphorylated alpha isoform of calcium/calmodulin dependent protein kinase type II (alphaCamKII) has been found in response to tissue injury. Additionally, alphaCamKII is essential for the induction of long term potentiation (LTP), an activity-dependent plasticity similar to central sensitization, in the hippocampus. The aim of this proposal is to address the hypothesis that alphaCamKII contributes to morphine tolerance at the spinal level.